This competing renewal application requests support for studies of AIDS pathogenesis in SCID mice reconstituted with human peripheral blood leukocytes (hu-PBL-SCID mice). The hu-PBL-SCID model supports replication of every HIV-1 and HIV-2 strain tested, and infected animals show early enhancement of human immunoglobulin (Ig) levels and later depletion of CD4 T cells in a viral strain- and dose-dependent manner. We now propose to study the mechanisms leading to both CD4 T cell depletion and human B cell activation. In particular, we will determine which region of the HIV genome determines rate of CD4 depletion, which we observe to differ between several molecular clones of virus; to correlate viral burden with rate of CD4 depletion, to characterize patient isolates at different stages of disease for their ability to cause CD4 depletion, and to characterize viral genomes recovered from hu-PBL-SCID mice. We will also study the state of T cell activation, and seek evidence for deletion or activation of specific T cells by analyzing T cell receptor Vbeta-usage. We will reconstitute hu-PBL-SCID mice with selected T cell- subpopulations to determine if CD4 depletion is autonomous or if it reflects cell-mediated cytotoxicity. We will examine several questions regarding B cell activation in the model; viz., (i) does virus directly activate B cells or must CD4 T cells participate; (ii) is B cell activation correlated with activation of CD4 T cells; (iii) is any part of the human Ig elevation related to HIV-1 specific responses; (iv) is there alteration of cytokine production that might prolong B cell activation (e.g., IL-6, IL-10); and (v) do all HIV-1 isolates equally stimulate elevation of human Ig? We will continue studies to improve the hu-PBL-SCID model, including substitution of the low NK double mutant strain, C.B-17 scid/scid, beige/beige as the PBL recipient; engraftment of myeloid precursors to provide a continuing source of monocytes; and use of newly developed gene knockout mice (e.g., RAG-1 defective) as improved recipients for human cells.